6-136682140-A-G

Position:

• chr6-136682140-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_005923.4(MAP3K5):​c.1253+12000T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0355 in 152,312 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.035 (95 hom., cov: 32)
• Consequence: MAP3K5 NM_005923.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.114

Genes affected

MAP3K5 (HGNC:6857): (mitogen-activated protein kinase kinase kinase 5) Mitogen-activated protein kinase (MAPK) signaling cascades include MAPK or extracellular signal-regulated kinase (ERK), MAPK kinase (MKK or MEK), and MAPK kinase kinase (MAPKKK or MEKK). MAPKK kinase/MEKK phosphorylates and activates its downstream protein kinase, MAPK kinase/MEK, which in turn activates MAPK. The kinases of these signaling cascades are highly conserved, and homologs exist in yeast, Drosophila, and mammalian cells. MAPKKK5 contains 1,374 amino acids with all 11 kinase subdomains. Northern blot analysis shows that MAPKKK5 transcript is abundantly expressed in human heart and pancreas. The MAPKKK5 protein phosphorylates and activates MKK4 (aliases SERK1, MAPKK4) in vitro, and activates c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) during transient expression in COS and 293 cells; MAPKKK5 does not activate MAPK/ERK. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0355 (5406/152312) while in subpopulation AMR AF= 0.0437 (668/15298). AF 95% confidence interval is 0.0409. There are 95 homozygotes in gnomad4. There are 2578 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 5406 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K5	NM_005923.4	c.1253+12000T>C		intron_variant		ENST00000359015.5	NP_005914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K5	ENST00000359015.5	c.1253+12000T>C		intron_variant		1	NM_005923.4	ENSP00000351908.4
MAP3K5	ENST00000698928.1	c.1580+12000T>C		intron_variant				ENSP00000514039.1

Frequencies

GnomAD3 genomes AF: 0.0355 AC: 5407 AN: 152194 Hom.: 95 Cov.: 32

Gnomad AFR AF: 0.0410

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0437

Gnomad ASJ AF: 0.0616

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00828

Gnomad FIN AF: 0.0211

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0361

Gnomad OTH AF: 0.0364

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0355 AC: 5406 AN: 152312 Hom.: 95 Cov.: 32 AF XY: 0.0346 AC XY: 2578 AN XY: 74480

Gnomad4 AFR AF: 0.0409

Gnomad4 AMR AF: 0.0437

Gnomad4 ASJ AF: 0.0616

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00829

Gnomad4 FIN AF: 0.0211

Gnomad4 NFE AF: 0.0361

Gnomad4 OTH AF: 0.0360

Alfa AF: 0.0360 Hom.: 26

Bravo AF: 0.0374

Asia WGS AF: 0.00809 AC: 30 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	11
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs7748892; hg19: chr6-137003278;